Human prostate-specific antigen essentially has been well known as a diagnostic marker in blood for patients with prostate carcinoma or hyperplasia, but recently, there has been advocated a new theory that human prostate-specific antigen acts to degrade specifically IGF (insulin-like growth factor) binding protein 3 to thereby cause increases in TGF levels in the prostate tissue, resulting in onset or progression of prostate carcinoma or development of prostate hyperplasia.
Accordingly, there exist great expectations that a drug being capable of inhibiting the said antigen would be effective in the treatment of prostate carcinoma and prostate hyperplasia.
Prostate-specific antigen (hereinafter referred to briefly as "PSA") was isolated in the form of .gamma.-seminoprotein from human seminal plasma by Hara et al. in 1971 (Jp. J. Legal Med., 25: 322, 1971), and was thereafter found to be identical to a substance purified from the prostate tissue by Wang et al., while the said antigen was also observed to be expressed specifically in the prostate (Invest. Urol., 17: 159-163, 1979 and Oncology, 99: 1, 1982), thus leading i-o establishment of the unified appellation "prostate-specific antigen". And Wang et al. discovered that patients with prostate hyperplasia or carcinoma show a raised blood level of PSA (Prostate, 2: 89-95, 1981), and currently, PSA has been put in wide use as a diagnostic marker in blood for such diseases.
PSA was long left unclassified for most of its actions in the living body, but Watt et al. determined its complete amino acid sequence and demonstrated that PSA is a protease of the kallikrein family which belongs to a kind of serine proteases (Proc. Natl. Acad. Sci. USA, 88: 3166-3170, 1986), They also clarified that PSA exhibits chymotrypsin activity.
Recently, Cohen et al. and Lee et al. found that the substrate in the living body for PSA is IGF binding protein 3 (J. Endocrinol., 142: 407-415, 1994, and J. Clin. Endocrinol, Metab., 7 1367-1372, 1994), and from this finding, it has come to be inferred that when rises in PSA levels in the prostate tissue is brought about by prostate carcinoma, etc., there takes place selective degradation of IGF binding protein 3, with the resultant increases in free IGF levels, which in turn may induce diseases, such as prostate carcinoma and prostate hyperplasia. When it is feasible to inhibit the protease activity of PSA, accordingly, this would offer a possibility for providing a therapeutic drug for prostate carcinoma, prostate hyperplasia, etc., but such attempt has never been made so far in the past.
In recent years, the number of patients with prostate carcinoma or prostate hyperplasia has been on an increasingly upward trend, and in view of the fact that there has been no effective therapeutic drug available, the development of a highly specific drug without adverse effects is strongly demanded. Under these circumstances, the present inventors, taking the view that development of an inhibitor against PSA would be a means for achieving the above-mentioned objective, decided to conduct investigation into the said PSA inhibitor.
As a result, the present. inventors determined the site where PSA cleavages IGF bidning protein 3 and subsequently carried out intensive research on amino acid sequences surrounding such cleavage site, and these led to the finding that a peptide consisting of Gly-Phe-Tyr-Lys-Lys-Lys-Gln-Ser-Arq elicits inhibitory activity against PSA, resulting in establishment of this research work and completion of the present invention.